In order that a pharmaceutical product can exert an intended effect, the activity of the pharmaceutical product should essentially be retained sufficiently at all of the steps of the handling of raw pharmaceutical chemicals, the blending, the filling, and the packaging, as well as during the period from the distribution to the termination of the use by patients. Not a few of compounds used as active ingredients are unstable against light and heat. Generally, the decomposition mechanism varies depending on the causative factors and the entity of the compounds, and is complicated. Therefore, it is very difficult to thoroughly elucidate such complicated mechanism so that the compound itself is modified for stabilization. Because photodecomposition in particular is involved in the specific property of a compound in absorptivity of a light, it is extremely difficult to modify the specific property while retaining an intended activity thereof. In such case that a compound that is unstable against light is used as an active ingredient, it should be necessary to design formulations to stabilize the compound.
Solution is affected prominently by light, and liquid formulations such as eye drops and injections should be protected from exposure to light. In eye drops, which are directly applied to mucosa, not only the decomposition of an active ingredient causes the reduction or elimination of medicinal efficacy following the decrease of the content, but also the resulting decomposed products may cause serious safety concerns on living biological organisms.
Measures to block the decomposition of ingredients unstable against light by formulation design include a method comprising using colored containers or labels or shielded bags, and a method comprising adding appropriate stabilizers to the formulations. However, the former method cannot essentially provide complete shielding and, additionally, the method cannot sufficiently protect the ingredients from exposure to light during the steps prior to the filling or during the period of the use by patients. Further, the Japanese Pharmacopoeia defines in the General Rules for Preparations that eye drops should not contain any insoluble particulate matters readily detectable with naked eye, and this definition is also applicable to injections. Because the appropriateness of eye drops or injections as pharmaceutical formulations is examined by visual inspection, the use of colored light-shielded containers which might affect the test of insoluble particulate matters should be limited.
On the other hand, it is difficult to determine the optimal conditions for stabilizers to block the decompositions because the photodecomposition mechanism is complicated and varies on the entity of ingredient. Additionally, the influences of the stabilizer on tissues should also be considered. For example, Japanese Patent Publication (kokoku) No. 23302/1995 describes a method for stabilizing an eye drop containing a drug unstable against light, which comprises incorporating boric acid and/or borax as well as polyhydric alcohol into the eye drop. Polyhydric alcohols, however, raise the viscosity of eye drops to increase the retention of the drug in eye mucosa, and enhance the irritation of the drug if the drug exhibits even a slight irritation. Eye irritation will also potentially induce the increase of lacrima amount to dilute active ingredients therein, thus resulting in no attainment of the intended effect.
Additionally, Japanese Patent Publication (kokai) No. 16724/1989 discloses an injection of vinca alkaloid of a dimer indole-dihydroindole compound. It is described therein that an injection prepared by dissolving the vinca dimer in a solution of EDTA, a preservative and acetate buffer, is stable in darkness at ambient temperature for nine months.